The purpose of this project is to characterize the immunopathologic abnormalities in patients with HIV infection and to determine the mechanisms underlying these abnormalities as well as to attempt to determine a better understanding of the nature of protective immunity to HIV. These studies are predominantly performed on samples of blood or lymphoid tissues obtained from healthy controls or patients with HIV infection, generally in the context of ongoing clinical research protocols. The SCID-hu PBL mouse model is utilized in some of these studies. A major emphasis of this project is to characterize the changes in the immune systems of patients with HIV infection during the natural history of the disease and the nature of the changes seen in the context of antiretroviral therapy. A variety of approaches are taken in this part of the project. The predominant effort is focused on laboratory evaluation of lymphocyte subpopulations utilizing flow cytometry and delineation of the T cell repertoire through genetic analysis. These studies are complemented by clinical protocols designed to evaluate the ability of the immune system to launch an immune response to recall antigens such as tetanus toxoid or primary antigens such as PhiX174 or keyhole limpet hemocyanin. A variety of immunologic abnormalities have been described in patients with HIV infection. Several of these are quite unique and provide windows through which to examine the regulation of the immune response and, in particular, the role of the CD4 T lymphocyte in regulation of the immune response. In this regard, the CD8 T cell limb of the immune system of patients with HIV infection is characterized by the presence of a population of cells that express increased levels of the activation markers HLA-DR and CD38. Studies are underway utilizing differential display techniques to determine whether or not these cells have arrested at a particular stage of the cell cycle and if so, by what mechanism. Patients with HIV infection progress to AIDS at different rates. One subset of HIV infected patients, long term non-progressors, appear to have developed mechanisms that are adequate to block disease progression. These individuals represent a small fraction of the patient population, but provide a unique opportunity to study mechanisms of protective immunity to HIV. By transferring the immune systems of these patients to SCID-hu mice and then examining the endogenous expression of HIV in the mice and/or the ability of the mice to withstand superinfection with unrelated strains of HIV, one is able to characterize which elements of the immune systems of these patients may be important in the control of virus. Once these elements are characterized one is able to embark upon experiments to attempt to reproduce them in the setting of progressive infection or as strategies for prophylactic vaccines.